EP2114890A2 - Verbindungen und zusammensetzungen als modulatoren der gpr119-aktivität - Google Patents

Verbindungen und zusammensetzungen als modulatoren der gpr119-aktivität

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Publication number
EP2114890A2
EP2114890A2 EP08713244A EP08713244A EP2114890A2 EP 2114890 A2 EP2114890 A2 EP 2114890A2 EP 08713244 A EP08713244 A EP 08713244A EP 08713244 A EP08713244 A EP 08713244A EP 2114890 A2 EP2114890 A2 EP 2114890A2
Authority
EP
European Patent Office
Prior art keywords
methylsulfonyl
tetrahydroisoquinolin
methyl
tetrahydroisoquinoline
propoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08713244A
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English (en)
French (fr)
Inventor
Phillip Alper
Mihai Azimioara
Christopher Cow
Robert Epple
Songchun Jiang
Gerald Lelais
Pierre-Yves Michellys
Truc Ngoc Nguyen
Lucas Westcott-Baker
Baogen Wu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
IRM LLC
Original Assignee
IRM LLC
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Application filed by IRM LLC filed Critical IRM LLC
Publication of EP2114890A2 publication Critical patent/EP2114890A2/de
Withdrawn legal-status Critical Current

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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/08—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with a hetero atom directly attached to the ring nitrogen atom
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of GPRl 19.
  • GPRl 19 is a G-protein coupled receptor (GPCR) that is mainly expressed in the pancreas, small intestine, colon and adipose tissue.
  • GPCR G-protein coupled receptor
  • the expression profile of the human GPRl 19 receptor indicates its potential utility as a target for the treatment of obesity and diabetes.
  • the novel compounds of this invention modulate the activity of GPRl 19 and are, therefore, expected to be useful in the treatment of GPRl 19-associated diseases or disorders such as, but not limited to, diabetes, obesity and associated metabolic disorders.
  • the present invention provides a compound of Formula I:
  • B is selected from C ⁇ -ioaryl, Ci.ioheteroaryl, C 3- i 2 cycloalkyl and C 3- sheterocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl of B is substituted with one to three radicals selected from -R 3 and -OX 3 R 3 ; wherein X 3 is selected from a bond and C
  • n and p are independently selected from 0, 1, 2 and 3;
  • q is selected from 0, 1 and 2;
  • m is selected from 1 , 2 and 3 ;
  • L is -Xi-A-X 2 -Bi-X 3 -; wherein A and Bi are independently selected from a bond, -O-, -S(O) 0-2 -, -C(O)-, -C(O)O-, -OC(O)-, -NR 4 -, -C(O)NR 4 -, -
  • Xi , X 2 and X 3 are independently selected from a bond, Ci_ 6 alkylene, C 2 . 6 alkenylene, C 3-8 cycloalkyl, C 6 - ioaryl, C 3-8 heterocycloalkyl and Ci- ⁇ heteroarylene; wherein said cycloalkyl, aryl, heterocycloalkyl or heteroaryl of L can be optionally substituted with up to 3 radicals independently selected from hydroxyl, halo, Ci -6 alkyl, Ci ⁇ alkoxy, halo-substituted-Ci.
  • each R 4 is independently selected from hydrogen, hydroxyl, halo, Ci -6 alkyl, halo-substituted-C].
  • X 4 NR 43 R 43 -X 4 NR 43 X 4 OR 43 , -X 4 C(O)OR 43 and -X 4 C(O)R 43 ; wherein X 4 is selected from a bond and Ci -4 alkylene; R 4a is selected from hydrogen and C
  • Ri is selected from Ci-ioalkyl, halo-substituted-Ci.
  • X 5 is selected from a bond and C
  • R 53 and R 5b are independently selected from hydrogen, Ci -6 alkyl, C 3 -i 2 cycloalkyl, halo-substituted-C
  • R 2a and R 2b are independently selected from halo, cyano, hydroxy, Ci-
  • R 5e and R 5 f are independently selected from hydrogen, Ci ⁇ alkyl, C 3 _i 2 cycloalkyl, halo-substituted-Ci. 6 alkyl, halo-substituted-Ci ⁇ cycloalkyl, C 6 _ioaryl and Ci.ioheteroaryl; wherein said aryl or heteroaryl of R 5e or R 5f can be optionally substituted with 1 to 3 radicals independently selected from Ci. 6 alkyl, Ci ⁇ alkoxy, halo-substituted-Ci -6 alkyl and halo-substituted-Ci. 6 alkoxy;
  • R 3 is selected from hydrogen, Ci.ioheteroaryl, C 6 -ioaryl, C 3 . sheterocycloalkyl, -C(O)OR 63 , -C(O)R 6a , -S(O) 0 .
  • R 6a is selected from a bond and Ci_ 6 alkylene
  • R 6a and R 6b are independently selected from hydrogen, Ci ⁇ alkyl, halo-substituted-Ci. 6 alkyl, C 3- i 2 cycloalkyl optionally substituted with C ⁇ alkyl, halo- substituted-Ci.
  • R 7 is selected from d- 8 alkyl, C 3 . 8 cycloalkyl, C 6 .ioaryl, Ci- l oheteroaryl, halo-substituted Ci -8 alkyl, halo-substituted-Cs-scycloalkyl, halo-substituted- C ⁇ -ioaryl and halo-substituted-C 6- ioheteroaryl; wherein said aryl, heteroaryl or heterocycloalkyl of R 3 is optionally substituted with 1 to 3 radicals independently selected from halo, cyano, -X 5a NR 8a R 8 b, -X 5a NR 8a R 9 , -X 5a NR 8a C(O)OR 8b , -X 53 C(O)OR 83 , -X 53 OR 83 , -X 5a OX 5b OR 8a ,
  • the present invention provides a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.
  • the present invention provides a method of treating a disease in an animal in which modulation of GPR 119 activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention provides the use of a compound of
  • the present invention provides a process for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof.
  • Alkyl as a group and as a structural element of other groups, for example halo-substituted- alkyl and alkoxy, can be straight-chained, branched, cyclic or spiro.
  • Ci- 6 alkoxy includes methoxy, ethoxy, and the like.
  • Halo-substituted alkyl includes trifluoromethyl, pentafluoroethyl, and the like.
  • Aryl means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms.
  • aryl can be phenyl or naphthyl, preferably phenyl.
  • Arylene means a divalent radical derived from an aryl group.
  • Heteroaryl is as defined for aryl where one or more of the ring members are a heteroatom.
  • Ci.ioheteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[l,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, lH-pyridin-2-onyl, 6-oxo-l,6-dihydro- pyridin-3-yl, etc.
  • C 6 -ioarylCo -4 alkyl means an aryl as described above connected via a alkylene grouping.
  • C 6 -ioarylCo- 4 alkyl includes phenethyl, benzyl, etc.
  • Heteroaryl also includes the N-oxide derivatives, for example, pyridine N-oxide derivatives with the following structure:
  • Cycloalkyl means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms indicated.
  • C 3 -iocycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • C 3-8 heterocycloalkyl as used in this application to describe compounds of the invention includes morpholino, pyrrolidinyl, piperazinyl, piperidinyl, piperidinylone, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, 2-oxo-pyrrolidin-l-yl, 2- oxo-piperidin-1-yl, etc.
  • GPRl 19 means G protein-coupled receptor 119 (GenBank ® Accession No.
  • GPRl 19 includes the human sequences found in GeneBank accession number AY288416, naturally-occurring allelic variants, mammalian orthologs, and recombinant mutants thereof.
  • Halogen (or halo) preferably represents chloro or fluoro, but can also be bromo or iodo.
  • Treatment refers to a method of alleviating or abating a disease and/or its attendant symptoms.
  • the present invention provides compounds, compositions and methods for the treatment of diseases in which modulation of GPRl 19 activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula
  • n and p are independently selected from 0, 1, 2 and 3;
  • q is selected from 0 and 1 ;
  • m is selected from 1, 2 and 3;
  • L is selected from C M O heteroarylene, -X 2 OX 3 -, -OX 2 X 3 -, -C(O)X 2 -, -
  • Ri is selected from C
  • X 5 is selected from a bond and Ci -3 alkylene;
  • R 53 and R 5 b are independently selected from hydrogen, Ci -6 alkyl, C 3 _i 2 cycloalkyl, halo-substituted-Ci -6 alkyl, C 6 -ioaryl-Co- 4 alkyl and Ci-ioheteroaryl; wherein said alkyl, cycloalky, aryl or heteroaryl of R 53 or R 5b can be optionally substituted with 1 to 3 radicals independently selected from hydrogen, hydroxy, Ci -6 alkyl, C 2 . 6 alkenyl, halo-substituted-C
  • R 5c and R 5( j are independently selected from hydrogen and Ci ⁇ alkyl;
  • R 2a and R 2b are independently selected from halo, methyl, cyano and nitro;
  • R 3 is selected from aryl, Ci-ioheteroaryl and -C(O)OR 63 ; wherein R 6a is selected from hydrogen, Ci -6 alkyl and C 3 _i 2 cycloalkyl optionally substituted with Ci- 4 alkyl; wherein said heteroaryl of R 3 is optionally substituted with 1 to 3 radicals independently selected from halo, cyano, -XsaNRgaRsb, -X 5 aNR 8a R 9 , -X 5a NRsaC(O)OR 8 b, -X 5a C(O)OR 8a , -X 5a OR 8a , -X 5a OX 5b OR 8a , -X 5a R 9 , C 1-6 alkyl, C,.
  • R 8a and R 8b are independently selected from hydrogen and Ci -6 alkyl; X 5a and X 5b are independently selected from a bond and Ci -4 alkylene; R 9 is selected from C 3- i 2 cycloalkyl, Cs.sheterocycloalkyl, Ci.ioheteroaryl and C 6- ioaryl-Co- 4 alkyl; wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 9 is optionally substituted with 1 to 3 radicals independently selected from halo, Ci -4 alkyl and Ci- 4 alkoxy; and
  • Y 1 is selected from CH and N.
  • L is selected from 3,5- 1 ,2,4-oxadiazolylene, ( 1 ,2,4- oxadiazol-5-yl)methoxy, (l,2,4-oxadiazol-5-yl)methyl, (l,2,4-oxadiazol-5-yl)ethyl, (1,2,4- oxadiazol-5-yl)propyl, phenoxy, phenoxy-methyl, -C(O)NHCH 2 -, -C(O)NH(CH 2 ) 2 -, - CH 2 OCH 2 -, -C(O)NH(CH 2 ),- -CH((CH 2 ) 2 OH)(CH 2 ) 3 -, -CH(CH 2 C(O)OCH 3 XCH 2 ),- - C(O)(CH 2 ),- -CH(OH)(CH 2 ),- -CH(Cl)(CH 2 ),-, -C(CH 3 )
  • Ri is selected from methyl-sulfonyl, butyl- sulfonyl, phenyl-sulfonyl, isopropyl-sulfonyl, ethyl-sulfonyl, ethenyl-sulfonyl, isopropoxy-carbonyl, benzyloxy-carbonyl, ethoxy-carbonyl, methyl-sulfonyl-ethyl, methoxy-carbonyl, t-butoxy-carbonyl and trifluoromethyl-sulfonyl.
  • R 3 is selected from t-butoxy-carbonyl, dimethylamino-carbonyl, methyl-sulfonyl, isopropoxy-carbonyl(ethyl)amino-methyl, isopropoxy-carbonyl-amino-methyl, benzyl(ethyl)amino-methyl, piperidinyl, quinazolinyl, isopropoxy-carbonyl, thieno[2,3-d]pyrimidin-4-yl, 4H-l,2,4-triazolyl, cyclopropoxy-carbonyl, (l,2,4-oxadiazol-5-yl), tetrazolyl, thiazolyl, triazolyl, pyrimidinyl, pyrazinyl, pyridinyl, phenyl, benzimidazolyl and pyridazinyl; wherein said cyclopropoxy, quinazolinyl,
  • n and p are independently selected from 0, 1, 2 and 3;
  • E 3 is selected from a bond, O and OCH 2 ;
  • L is selected from Ci.ioheteroarylene, -X 2 OX 3 -, -OX 2 X 3 -, -C(O)X 2 -,
  • X 2 X 3 -, -OX 2 O-, -OX 2 C(O)X 3 -, -OX 2 C(O)OX 3 -, -CR 4 (NR 4 R 4 )X 2 -, - CR 4 (NR 4 C(O)R 4 )X 2 -, -Q NOR 4 )X 2 -, -NR 4 C(O)X 2 -, -C(O)NR 4 X 2 -, -NR 4 X 2 -, N(C(O)R 4 )X 2 - and -OC(O)NR 4 X 2 -; wherein X 2 and X 3 are independently selected from a bond, Ci. 6 alkylene, C 2 .
  • R 4 is selected from hydrogen and Ci- ⁇ alkyl; wherein any methylene of L can have the hydrogens replaced by a radical selected from halo, hydroxy, Ci -4 alkyl, Ci- 4 alkoxy, hydroxy-substituted-Ci -4 alkyl and -CR 4 R 4 C(O)OR 4 ;
  • Ri is selected from Q.ioalkyl, halo-substituted-Ci.ioalkyl, C 6- ioaryl, Ci- l oheteroaryl, -X 5 S(O) 0-2 R 53 , -X 5 C(O)OR 5a , -X 5 C(O)R 53 , and -X 5 C(O)NR 5a R 5b ; wherein X 5 is selected from a bond and Ci -3 alkylene; R 5a and R 5b are independently selected from hydrogen, C) -6 alkyl, C 3 _i 2 cycloalkyl, halo-substituted-Ci- 6 alkyl, C 6 -ioaryl-Co -4 alkyl and Ci-ioheteroaryl; wherein said alkyl, cycloalkyl, aryl or heteroaryl of R 5a or R 5b can be optionally substituted with 1 to 3 radicals independently selected from hydrogen,
  • R 2a and R 2b are independently selected from halo, methyl, cyano and nitro;
  • R 3 is selected from hydrogen, SO 2 R 63 , C ⁇ -ioaryl, Ci-ioheteroaryl and -
  • L is selected from 3,5- 1 ,2,4-oxadiazolylene, ( 1 ,2,4- oxadiazol-5-yl)methoxy, ( 1 ,2,4-oxadiazol-5-yl)methyl, (l,2,4-oxadiazol-5-yl)ethyl, (1,2,4- oxadiazol-5-yl)propyl, phenoxy, phenoxy-methyl, -C(O)NHCH 2 -, -C(O)NH(CH 2 ) 2 -, - CH 2 OCH 2 -, -C(O)NH(CH 2 ) 3 -, -CH((CH 2 ) 2 OH)(CH 2 ) 3 - -CH(CH 2 C(O)OCH 3 )(CH 2 ) 3 - - C(O)(CHz) 3 - -CH(OH)(CH 2 )J-, -CH(C1)(CH 2 ) 3
  • Ri is selected from methyl-sulfonyl, butyl - sulfonyl, phenyl- sulfonyl, isopropyl-sulfonyl, ethyl-sulfonyl, ethenyl-sulfonyl, isopropoxy-carbonyl, benzyloxy-carbonyl, ethoxy-carbonyl, methyl-sulfonyl-ethyl, methoxy-carbonyl, t-butoxy-carbonyl and trifluoromethyl-sulfonyl.
  • R 3 is selected from t-butoxy-carbonyl, dimethylamino-carbonyl, methyl-sulfonyl, isopropoxy-carbonyl(ethyl)amino-methyl, isopropoxy-carbonyl-amino-methyl, benzyl(ethyl)amino-methyl, piperidinyl, quinazolinyl, isopropoxy-carbonyl, thieno[2,3-d]pyrimidin-4-yl, 4H-l,2,4-triazolyl, cyclopropoxy-carbonyl, (l,2,4-oxadiazol-5-yl), tetrazolyl, thiazolyl, triazolyl, pyrimidinyl, pyrazinyl, pyridinyl, phenyl, benzimidazolyl and pyridazinyl; wherein said cyclopropoxy, quinazolinyl,
  • n and p are independently selected from 0, 1, 2 and 3;
  • L is selected from C M oheteroarylene, -X 2 OX 3 -, -OX 2 X 3 -, -C(O)X 2 -, -
  • X 2 X 3 -, -OX 2 O-, -OX 2 C(O)X 3 -, -OX 2 C(O)OX 3 -, -CR 4 (NR 4 R 4 )X 2 -, - CR 4 (NR 4 C(O)R 4 )X 2 -, -Q NOR 4 )X 2 -, -NR 4 C(O)X 2 -, -C(O)NR 4 X 2 -, -NR 4 X 2 -, - N(C(O)R 4 )X 2 - and -OC(O)NR 4 X 2 -; wherein X 2 and X 3 are independently selected from a bond, Ci -6 alkylene, C 2 .
  • R 4 is selected from hydrogen and Ci_ 6 alkyl; wherein any methylene of L can have the hydrogens replaced by a radical selected from halo, hydroxy, Ci -4 alkyl, Ci- 4 alkoxy, hydroxy-substituted-Ci -4 alkyl and -CR 4 R 4 C(O)OR 4 ;
  • Ri is selected from Ci.ioalkyl, halo-substituted-Ci-ioalkyl, C 6- ioaryl, Ci. loheteroaryl, -X 5 S(0)o. 2 R 5 a, -X 5 C(O)OR 53 , -X 5 C(O)R 53 , and -X 5 C(O)NR 5a R 5b ; wherein X 5 is selected from a bond and Ci -3 alkylene; R 53 and R 5b are independently selected from hydrogen, Ci -6 alkyl, C 3- i 2 cycloalkyl, halo-substituted-C
  • R 2a and R 2b are independently selected from halo, methyl, cyano and nitro;
  • R 3 is selected from aryl, Q-ioheteroaryl and -C(O)OR 6a ; wherein R 6a is selected from hydrogen, Ci -6 alkyl and C 3- i 2 cycloalkyl optionally substituted with Ci- 4 alkyl; wherein said heteroaryl of R 3 is optionally substituted with 1 to 3 radicals independently selected from halo, cyano, -X5 a NR 8a R 8 b, -Xs 3 NR 83 Rg, -X5 a NRg a C(O)OR 8 b, -X 5a C(O)OR 8a , -X 5a OR 8a , -X 5a OX 5b OR 83 , -X 53 R 9 , C,.
  • R 8a and R 8b are independently selected from hydrogen and Ci_ 6 alkyl;
  • X 5a and X 5b are independently selected from a bond and Ci -4 alkylene;
  • R 9 is selected from C 3- i 2 cycloalkyl, C 3-8 heterocycloalkyl, Ci-ioheteroaryl and C 6- ioaryl-Co- 4 alkyl; wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 9 is optionally substituted with 1 to 3 radicals independently selected from halo, Cj. 4 alkyl and Q- 4 alkoxy.
  • L is selected from 3,5-1 ,2,4-oxadiazolylene, ( 1 ,2,4- oxadiazol-5-yl)methoxy, ( 1 ,2,4-oxadiazol-5-yl)methyl, (l,2,4-oxadiazol-5-yl)ethyl, (1,2,4- oxadiazol-5-yl)propyl, phenoxy, phenoxy-methyl, -C(O)NHCH 2 -, -C(O)NH(CH 2 ) 2 -, - CH 2 OCH 2 -, -C(O)NH(CH 2 ) 3 -, -CH((CH 2 ) 2 OH)(CH 2 ) 3 - -CH(CH 2 C(O)OCH 3 )(CH 2 )3-, - C(O)(CH 2 ) 3 - -CH(OH)(CH 2 )J-, -CH(C1)(CH 2 ) 3
  • Ri is selected from methyl-sulfonyl, butyl- sulfonyl, phenyl-sulfonyl, isopropyl-sulfonyl, ethyl-sulfonyl, ethenyl-sulfonyl, methyl- sulfonyl-ethyl, isopropoxy-carbonyl, benzyloxy-carbonyl, ethoxy-carbonyl, methoxy- carbonyl, t-butoxy-carbonyl and trifluoromethyl-sulfonyl.
  • R 3 is selected from t-butoxy-carbonyl, dimethylamino-carbonyl, methyl-sulfonyl, isopropoxy-carbonyl(ethyl)amino-methyl, isopropoxy-carbonyl-amino-methyl, benzyl(ethyl)amino-methyl, piperidinyl, quinazolinyl, isopropoxy-carbonyl, thieno[2,3-d]pyrimidin-4-yl, 4H-l,2,4-triazolyl, cyclopropoxy-carbonyl, (l,2,4-oxadiazol-5-yl), tetrazolyl, thiazolyl, triazolyl, pyrimidinyl, pyrazinyl, pyridinyl, phenyl, benzimidazolyl and pyridazinyl; wherein said cyclopropoxy, quinazolinyl,
  • n and p are independently selected from 0, 1, 2 and 3;
  • L is selected from C M oheteroarylene, -X 2 OX 3 -, -OX 2 X 3 -, -C(O)X 2 -, -
  • Ri is selected from Q.ioalkyl, halo-substituted-Ci-ioalkyl, C ⁇ -ioaryl, Q- loheteroaryl, -X 5 S(O) 0 - 2 R 5a , -X 5 C(O)OR 53 , -X 5 C(O)R 53 , and -X 5 C(O)NR 5a R 5b ; wherein
  • X 5 is selected from a bond and Q -3 alkylene;
  • R 53 and R 5b are independently selected from hydrogen, Q -6 alkyl, C 3- i 2 cycloalkyl, halo-substituted-Ci- ⁇ alkyl, C 6 .ioaryl-Co -4 alkyl and
  • Ci-ioheteroaryl wherein said alkyl, cycloalkyl, aryl or heteroaryl of R 53 or R 5b can be optionally substituted with 1 to 3 radicals independently selected from hydrogen, hydroxy, Q. 6 alkyl, C 2-6 alkenyl, halo-substituted-Ci -6 alkyl, halo-substituted-Q -6 alkoxy -
  • NR5cR 5 d -C(O)OR 5 C and C6-ioaryl-Co -4 alkyl; wherein R 5c and R 5 d are independently selected from hydrogen and Q. 6 alkyl;
  • R 2a and R 2b are independently selected from halo, methyl, cyano and nitro;
  • Gi, G 2 and G 3 are independently selected from N and CH; with the proviso that at least one of Gi, G 2 or G 3 is N;
  • [0071] is selected from aryl, Ci.ioheteroaryl and -C(O)O R 6a ; wherein R 6a is selected from hydrogen, Ci -6 alkyl and C 3- i 2 cycloalkyl optionally substituted with Ci- 4 alkyl; wherein said heteroaryl of R 3 is optionally substituted with 1 to 3 radicals independently selected from halo, cyano, -X 5a NR 8a R 8 b, -X 5a NR 8a R9, -X 5a NR 8a C(O)OR 8 b, -X 5a C(O)OR 8a , -X 5a OR 8a , -X 5a OX 5b OR 8a , -X 53 R 9 , C,.
  • R 8a and R 8b are independently selected from hydrogen and Ci -6 alkyl;
  • X 5a and X 5b are independently selected from a bond and Ci -4 alkylene;
  • R 9 is selected from C 3- i 2 cycloalkyl, C ⁇ heterocycloalkyl, Ci-ioheteroaryl and C 6 _ioaryl-Co- 4alkyl; wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 9 is optionally substituted with 1 to 3 radicals independently selected from halo, Ci -4 alkyl and Ci. 4alkoxy.
  • L is selected from 3,5- 1 ,2,4-oxadiazolylene, ( 1 ,2,4- oxadiazol-5-yl)methoxy, (l,2,4-oxadiazol-5-yl)methyl, (l,2,4-oxadiazol-5-yl)ethyl, (1,2,4- oxadiazol-5-yl)propyl, phenoxy, phenoxy-methyl, -C(O)NHCH 2 -, -C(O)NH(CH 2 ) 2 - - CH 2 OCH 2 -, -C(O)NH(CH 2 ) 3 - -CH((CH 2 ) 2 OH)(CH 2 ) 3 -, -CH(CH 2 C(O)OCH 3 )(CH 2 ) 3 -, - C(O)(CHz) 3 -, -CH(OH)(CH 2 ) 3 -, -CH(C1)(CH 2 ) 3
  • Ri is selected from methyl-sulfonyl, butyl - sulfonyl, phenyl-sulfonyl, isopropyl-sulfonyl, ethyl-sulfonyl, ethenyl-sulfonyl, methyl- sulfonyl-ethyl, isopropoxy-carbonyl, benzyloxy-carbonyl, ethoxy-carbonyl, methoxy- carbonyl, t-butoxy-carbonyl and trifluoromethyl-sulfonyl.
  • R 3 is selected from t- butoxy-carbonyl, dimethylamino-carbonyl, methyl-sulfonyl, isopropoxy- carbonyl(ethyl)amino-methyl, isopropoxy-carbonyl-amino-methyl, benzyl(ethyl)amino- methyl, piperidinyl, quinazolinyl, isopropoxy-carbonyl, thieno[2,3-d]pyrimidin-4-yl, 4H- 1,2,4-triazolyl, cyclopropoxy-carbonyl, (l,2,4-oxadiazol-5-yl), tetrazolyl, thiazolyl, triazolyl, pyrimidinyl, pyrazinyl, pyridinyl, phenyl, benzimidazolyl and pyridazinyl; wherein said cyclopropoxy, quina
  • Compounds of the invention modulate the activity of GPRl 19 and, as such, are useful for treating diseases or disorders in which the activity of GPRl 19 contributes to the pathology and/or symptomology of the disease.
  • This invention further provides compounds of this invention for use in the preparation of medicaments for the treatment of diseases or disorders in which GPRl 19 activity contributes to the pathology and/or symptomology of the disease.
  • Type II diabetes The resultant pathologies of Type II diabetes are impaired insulin signaling at its target tissues and failure of the insulin-producing cells of the pancreas to secrete an appropriate degree of insulin in response to a hyperglycemic signal.
  • Current therapies to treat the latter include inhibitors of the ⁇ -cell ATP-sensitive potassium channel to trigger the release of endogenous insulin stores, or administration of exogenous insulin. Neither of these achieves accurate normalization of blood glucose levels and both carry the risk of inducing hypoglycemia. For these reasons, there has been intense interest in the development of pharmaceuticals that function in a glucose-dependent action, i.e. potentiators of glucose signaling.
  • Physiological signaling systems which function in this manner are well-characterized and include the gut peptides GLP-I, GIP and PACAP. These hormones act via their cognate G-protein coupled receptor to stimulate the production of cAMP in pancreatic ⁇ -cells. The increased cAMP does not appear to result in stimulation of insulin release during the fasting or pre-prandial state.
  • a series of biochemical targets of cAMP signaling including the ATP-sensitive potassium channel, voltage-sensitive potassium channels and the exocytotic machinery, are modified in such a way that the insulin secretory response to a postprandial glucose stimulus is markedly enhanced.
  • ⁇ -cell GPCRs including GPRl 19
  • GPRl 19 Some ⁇ -cell GPCRs, including GPRl 19, are also present in the hypothalamus where they modulate hunger, satiety, decrease food intake, controlling or decreasing weight and energy expenditure. Hence, given their function within the hypothalamic circuitry, agonists or inverse agonists of these receptors mitigate hunger, promote satiety and therefore modulate weight.
  • an embodiment of the invention is a method for treatment of a metabolic disease and/or a metabolic-related disorder in an individual comprising administering to the individual in need of such treatment a therapeutically effective amount of a compound of the invention or a pharmaceutical composition thereof.
  • the metabolic diseases and metabolic-related disorders are selected from, but not limited to, hyperlipidemia, type 1 diabetes, type 2 diabetes mellitus, idiopathic type 1 diabetes (Type Ib), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (e.g., hyperlipidemia, type 1 diabetes, type 2 diabetes mellitus, idiopathic type 1 diabetes (Type Ib), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease,
  • necrosis and apoptosis dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance.
  • GPRl 19 activity modulators derived from increasing levels of GIP and PPY. For example, neuroprotection, learning and memory, seizures and peripheral neuropathy.
  • GLP-I and GLP-I receptor agonists have been shown to be effective for treatment of neurodegenerative diseases and other neurological disorders.
  • GLP-I and exendin-4 have been shown to stimulate neurite outgrowth and enhance cell survival after growth factor withdrawal in PC 12 cells. In a rodent model of neurodegeneration, GLP-I and exendin-4 restore cholinergic marker activity in the basal forebrain.
  • GLP-I and exendin-4 also reduce the levels of amyloid- ⁇ peptide in mice and decrease amyloid precursor protein amount in cultured PC 12 cells.
  • GLP-I receptor agonists have been shown to enhance learning in rats and the GLP-I receptor knockout mice show deficiencies in learning behavior. The knockout mice also exhibit increased susceptibility to kainate- induced seizures which can be prevented by administration of GLP-I receptor agonists.
  • GLP-I and exendin-4 has also been shown to be effective in treating pyridoxine- induced peripheral nerve degeneration, an experimental model of peripheral sensory neuropathy.
  • Glucose-dependent insulinotropic polypeptide has also been shown to have effects on proliferation of hippocampal progenitor cells and in enhancing sensorimotor coordination and memory recognition.
  • GLP-2 GLP-2 and short bowel syndrome (SBS).
  • SBS short bowel syndrome
  • GLP-2 GLP-2 is a trophic hormone that plays an important role in intestinal adaptation. Its role in regulation of cell proliferation, apoptosis, and nutrient absorption has been well documented.
  • Short bowel syndrome is characterized by malabsorption of nutrients, water and vitamins as a result of disease or surgical removal of parts of the small intestine (eg. Crohn's disease). Therapies that improve intestinal adaptation are thought to be beneficial in treatment of this disease.
  • phase II studies in SBS patients have shown that teduglutide, a GLP-2 analog, modestly increased fluid and nutrient absorption.
  • GLP-I GLP-I
  • GIP calcitonin related gene peptide
  • osteoporosis a disease that is caharacterized by reduced bone mineral density and thus GLP-I induced increase in calcitonin might be therapeutically beneficial.
  • GIP has been reported to be involved in upregulation of markers of new bone formation in osetoblasts including collagen type I mRNA and in increasing bone mineral density. Like GLP-I, GIP has also been shown to inhibit bone resorption.
  • GPRl 19 activity modulators derived from increasing levels of GIP and PPY. For example, PPY and gastric emptying. GPRl 19 located on the pancreatic polypeptide (PP) cells of the islets has been implicated in the secretion of PPY. PPY has been reported to have profound effects on various physiological processes including modulation of gastric emptying and gastrointestinal motility.
  • PPY can suppress food intake by changing the expression of hypothalamic feeding-regulatory peptides.
  • PP-overexpressing mice exhibited the thin phenotype with decreased food intake and gastric emptying rate.
  • the present invention further provides a method for preventing or ameliorating the symptamology of any of the diseases or disorders described above in a subject in need thereof, which method comprises administering to said subject a therapeutically effective amount (See, "Administration and Pharmaceutical Compositions", infra) of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount See, "Administration and Pharmaceutical Compositions", infra
  • the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.
  • Administration and Pharmaceutical Compositions are examples of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents.
  • a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5mg/kg per body weight.
  • An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5mg to about lOOmg, conveniently administered, e.g. in divided doses up to four times a day or in retard form.
  • Suitable unit dosage forms for oral administration comprise from ca. 1 to 50mg active ingredient.
  • Compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods.
  • oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrollidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose, sucrose,
  • compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions.
  • the compositions can be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they can also contain other therapeutically valuable substances.
  • Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier.
  • a carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • Matrix transdermal formulations can also be used.
  • Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations).
  • Anti-obesity agents include, but are not limited to, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4 agonists, cholescystokinin-A (CCK-A) agonists, serotonin and norepinephrine reuptake inhibitors (for example, sibutramine), sympathomimetic agents, ⁇ 3 adrenergic receptor agonists, dopamine agonists (for example, bromocriptine), melanocyte-stimulating hormone receptor analogs, cannabinoid 1 receptor antagonists [for example, compounds described in WO2006/047516), melanin concentrating hormone antagonists, leptons (the OB protein), leptin analogues, le
  • dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.
  • a combined preparation or pharmaceutical composition can comprise a compound of the invention as defined above or a pharmaceutical acceptable salt thereof and at least one active ingredient selected from:
  • anti-diabetic agents such as insulin, insulin derivatives and mimetics; insulin secretagogues such as the sulfonylureas, e.g., Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; insulin sensitizer such as protein tyrosine phosphatase- IB (PTP-IB) inhibitors such as PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors such as SB- 517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR ligands such as GW-0791 and AGN- 194204; sodium-dependent glucose co-transporter inhibitors such as T-1095; glycogen phosphorylase A inhibitors such as BAY
  • hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A
  • HMG-CoA reductase inhibitors e.g., lovastatin and related compounds such as those disclosed in U.S. Pat. No. 4,231,938, pitavastatin, simvastatin and related compounds such as those disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171, pravastatin and related compounds such as those disclosed in U.S. Pat. No.4,346,227, cerivastatin, mevastatin and related compounds such as those disclosed in U.S. Pat. No. 3,983,140, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and related statin compounds disclosed in U.S. Pat. No.
  • phosphinic acid compounds useful in inhibiting HMG CoA reductase suitable for use herein are disclosed in GB 2205837; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; cholestyramine; fibrates; nicotinic acid and aspirin;
  • an anti-obesity agent or appetite regulating agent such as a CBl activity modulator, melanocortin receptor (MC4R) agonists, melanin-concentrating hormone receptor (MCHR) antagonists, growth hormone secretagogue receptor (GHSR) antagonists, galanin receptor modulators, orexin antagonists, CCK agonists, GLP-I agonists, and other Pre-proglucagon-derived peptides; NPYl or NPY5 antagonsist, NPY2 and NPY4 modulators, corticotropin releasing factor agonists, histamine receptor-3 (H3) modulators, aP2 inhibitors, PPAR gamma modulators, PPAR delta modulators, acetyl- CoA carboxylase (ACC) inihibitors, 11- ⁇ -HSD-l inhibitors, adinopectin receptor modulators; beta 3 adrenergic agonists, such as AJ9677 (Takeda/
  • a thyroid receptor beta modulator such as a thyroid receptor ligand as disclosed in WO 97/21993 (U. CaI SF), WO 99/00353 (KaroBio) and GB98/284425 (KaroBio), a SCD-I inhibitor as disclosed in WO2005011655, a lipase inhibitor, such as orlistat or ATL-962 (Alizyme), serotonin receptor agonists, (e.g., BVT- 933 (Biovitrum)), monoamine reuptake inhibitors or releasing agents, such as fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, dexamphetamine, phentermine, phenylpropanolamine or
  • anti-hypertensive agents such as loop diuretics such as ethacrynic acid, furosemide and torsemide; diuretics such as thiazide derivatives, chlorithiazide, hydrochlorothiazide, amiloride; angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolapril; inhibitors of the Na-K- ATPase membrane pump such as digoxin; neutralendopeptidase (NEP) inhibitors e.g.
  • loop diuretics such as ethacrynic acid, furosemide and torsemide
  • diuretics such as thiazide derivatives, chlorithiazide, hydrochlorothiazide, amiloride
  • ECE inhibitors e.g. SLV306
  • ACE/NEP inhibitors such as omapatrilat, sampatrilat and fasidotril
  • angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan
  • renin inhibitors such as aliskiren, terlakiren, ditekiren, RO 66-1132, RO-66-1168
  • beta-adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol
  • inotropic agents such as digoxin, dobutamine and milrinone
  • calcium channel blockers such as digoxin, dobutamine and milrinone
  • thrombin inhibitors such as Ximelagatran
  • aldosterone inhibitors such as anastrazole, fadrazole, eplerenone
  • a chemotherapeutic agent such as aromatase inhibitors e.g. femara, anti- estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, antineoplastic antimetabolites, platin compounds, compounds decreasing the protein kinase activity such as a PDGF receptor tyrosine kinase inhibitor preferably Imatinib ( ⁇ N- ⁇ 5-[4-(4-methyl-piperazino-methyl)-benzoylarnido]-2- methylphenyl ⁇ -4-(3-pyridyl)-2-pyrimidine-amine ⁇ ) described in the European patent application EP-A-O 564 409 as example 21 or 4-Methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-yla
  • an agent for treating erectile dysfunction e.g., dopaminergic agents, such as apomorphine
  • ADD/ ADHD agents e.g., Ritalin®, Strattera®, Concerta® and Adderall®
  • an agent for treating alcoholism such as opioid antagonists (e.g., naltrexone (also known under the tradename ReVia®) and nalmefene), disulfiram (also known under the tradename Antabuse®), and acamprosate (also known under the tradename Campral®)).
  • opioid antagonists e.g., naltrexone (also known under the tradename ReVia®) and nalmefene
  • disulfiram also known under the tradename Antabuse®
  • acamprosate also known under the tradename Campral®
  • COX-2 inhibitors COX-2 inhibitors
  • antidepressants e.g., fluoxetine hydrochloride (Prozac®)
  • cognitive improvement agents e.g., donepezil hydrochloride (Aircept®) and other acetylcholinesterase inhibitors
  • neuroprotective agents e.g., memantine
  • antipsychotic medications e.g., ziprasidone (Geodon®), risperidone (Risperdal®), and olanzapine (Zyprexa®)
  • the invention also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • a pharmaceutical combination e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • the kit can comprise instructions for its administration.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound of Formula I and a co- agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g.
  • a compound of Formula I and a co-agent are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.
  • cocktail therapy e.g. the administration of 3 or more active ingredients.
  • the present invention also includes processes for the preparation of compounds of the invention.
  • reactive functional groups for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Conventional protecting groups can be used in accordance with standard practice, for example, see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.
  • a compound of Formula I can be prepared by reacting a compound of formula 2 with a compound of formula 3 in the presence of a suitable solvent (for example, methylene chloride, and the like) and a suitable base (for example, pyridine, triethylamine, and the like). The reaction proceeds at a temperature of about O 0 C to about 5O 0 C and can take up to 24 hours to complete.
  • a suitable solvent for example, methylene chloride, and the like
  • a suitable base for example, pyridine, triethylamine, and the like.
  • a compound of Formula I can be prepared by reacting a compound of formula 4 with a compound of formula 5, where Y is a leaving group (for example OMs, Br and the like) and X is O or N and the like, in the presence of a suitable solvent (for example, dimethylformamide, and the like) and a suitable base (for example, pyridine, triethylamine, K 2 CO 3 and the like).
  • a suitable solvent for example, dimethylformamide, and the like
  • a suitable base for example, pyridine, triethylamine, K 2 CO 3 and the like.
  • a compound of Formula I can be prepared by reacting a compound of formula 5 with a compound of formula 7 in the presence of a suitable solvent (for example, dimethylformamide, and the like) and a suitable base (for example, pyridine, triethylamine, K 2 CO 3 and the like). The reaction proceeds at a temperature of about O 0 C to about 16O 0 C and can take up to 24 hours to complete.
  • a suitable solvent for example, dimethylformamide, and the like
  • a suitable base for example, pyridine, triethylamine, K 2 CO 3 and the like.
  • a compound of Formula I can be prepared by reacting a compound of formula 8 with a compound of formula 9 (where Q is a halogen, OMs, OTf and the like; Z is H, alkyl, and the like) in the presence of a suitable solvent (for example, dioxane, water and the like), a suitable base (for example, Na 2 CO 3 and the like) and a catalyst ((Pd (PPh 3 ) 4 and the like). The reaction proceeds at a temperature of about O 0 C to about 16O 0 C and can take up to 24 hours to complete.
  • a suitable solvent for example, dioxane, water and the like
  • a suitable base for example, Na 2 CO 3 and the like
  • a catalyst (Pd (PPh 3 ) 4 and the like).
  • a compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively.
  • a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
  • a suitable base e.g., ammonium hydroxide solution, sodium hydroxide, and the like.
  • a compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).
  • Compounds of the invention in unoxidized form can be prepared from N- oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 0 C.
  • a suitable inert organic solvent e.g. acetonitrile, ethanol, aqueous dioxane, or the like
  • Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).
  • a suitable carbamylating agent e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like.
  • Hydrates of compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
  • Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
  • the diastereomers can be separated by chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons,
  • the compounds of Formula I can be made by a process, which involves:
  • Example 1 The present invention is further exemplified, but not limited, by the following Examples that illustrate the preparation of compounds of the invention.
  • Step B 2-(Methylsulfonyl)-l,2,3,4-tetrahydroisoquinolin-6-ol (3).
  • aquousl0% NaOH 20 mL
  • the mixture was cooled to it, poured into ethyl acetate (30 mL) and the organics were separated, washed with saturated NH 4 Cl, brine, dried and filterd.
  • Step A 2-(Methylsulfonyl)-l,2,3,4-tetrahydroisoquinolin-7-ol.
  • Step B tert-Butyl 4-(2-(2-(methylsulfonyl)-l,2,3,4-tetrahydroisoquinolin-
  • Step A l-(Methylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl methanesulfonate (6).
  • 6-methoxy- 1,2,3,4- tetrahydroquinoline (5) 500 mg, 3.1 mmol
  • dichloromethane (20 mL) was added triethylamine (864 ⁇ L, 6.2 mmol).
  • Methanesulfonyl choride (482 uL, 6.2 mmol) was added slowly at O 0 C and the mixture was stirred for 3 h.
  • Step B l-(Methylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-ol .
  • a solution of 6 (200 mg, 0.88 mmol) in dichloromethane was cooled to -78 0 C in a dry ice/acetone bath.
  • BBr 3 in dichloromethane (2.4 mL, 1.0 M, 2.4 mmol) was added dropwise. The cooling bath was removed and the mixture was allowed to warm to rt. After stirring for 1 h at rt, saturated sodium bicarbonate was added and the mixture was extracted with dichloromethane. The organics were combined and washed with brine, dried, concentrated under reduced pressure.
  • Step C tert-Buty ⁇ 4-(3-(l-(methylsulfonyl)-l,2,3,4-tetrahydroquinolin-6- yloxy)propyl)piperidine-l-carboxylate.
  • the title compound was synthesized according to Example 1 from the corresponding l-(methylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-ol and tert-butyl 4-(3-(methylsulfonyloxy)propyl)piperidine-l-carboxylate.
  • Step A Benzyl 6-hydroxy-3,4-dihydroisoquinoline-2(lH)-carboxylate
  • Step B Benzyl 6-(2-(l-(isopropoxycarbonyl)piperidin-4-yl)ethoxy)-3,4- dihydroisoquinoline-2(lH)-carboxylate (9).
  • Intermediate 9 was synthesized according to Example 1 from the corresponding benzyl 6-hydroxy-3,4-dihydroisoquinoline-2(lH)- carboxylate (8) (500 mg, 1.8 mmol) and isopropyl 4-(2-(methylsulfonyloxy)- ethyl) ⁇ iperidine-l-carboxylate (4).
  • Step C Isopropyl 4-(2-(l,2,3,4-tetrahydroisoquinolin-6- yloxy)ethyl)piperidine-l-carboxylate (10).
  • Intermediate 9 (864 mg, 1.8 mmol) was dissolved in methanol (30 mL) and palladium on carbon (10%, 300 mg) was added. The mixture was stirred under a hydrogen atmosphere for 30 minutes and then filtered through Celite. Removal of solvent under reduced pressure afforded intermediate 10 as a yellow oil.
  • MS calcd. for [M+H] + C 20 H 30 N 2 O 3 : 347.2; found: 347.2.
  • Step B Isopropyl 4-(5-(chloromethyl)-l,2,4-oxadiazol-3-yl)piperidine-l- carboxylate (13).
  • 11 (30 mg, 0.1 mmol) in dichloromethane (3 mL) was added triethylamine (10OuL, 0.7 mmol) and the mixture was stirred at rt for 10 minutes.
  • Chloroacetyl chloride 50 uL, 0.62 mmol
  • Step A 3-(Piperidin-4-yl)propan-l-ol hydrochloride (24b).
  • Concentrated HCl (25 mL) was added followed by addition of PtO 2 (200 mg).
  • the mixture was subjected to H 2 (60 psi) in a Parr shaker for 2Oh. Then solvents were removed under reduced pressure and the product was dried in vacuo overnight to afford intermediate 24b.
  • Step B 3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)propan-l-ol (24c).
  • a round bottom flask was charged with 3-(piperidin-4-yl)propan-l-ol hydrochloride (2) (1.8 g, 10 mmol), 2-chloro-5-ethylpyrimidine (1.44 g, mmol), Cs 2 CO 3 (7 g, 10.1 mmol) and DMF (25 mL).
  • the mixture was heated at 12O 0 C for 20 h. Then it was cooled to it and EtOAc (100 mL) was added followed by water (50 mL).
  • Step C 3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)propyl methanesulfonate (24d).
  • Et 3 N (1 mL, 7.2 mmol
  • MsCl (0.41 mL) was added slowly. After the addition was completed, the reaction mixture was stirred for 3 h at rt, then quenched with water.
  • Step D 6-(3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2-
  • Example 25 was prepared by analogous method from example 24.
  • Example 26 was prepared by analogous method from example 24.
  • Step B Intermediate 26a (5.45 g, 22.3 mmol) was placed in a flask and cold H 2 SO 4 ZAcOH solution (3:2 v/v, 50 ml) was added, followed by solid paraformaldehyde (1.36 g, 45.3 mmol). The mixture was then stirred at 45 0 C for 3 h. The mixture was poured into ice and extracted with CH 2 Cl 2 . The organics were washed with sat.
  • Step C A round bottom flask was charged with intermediate 26b (3.93 g,
  • Step A Commercially available (piperidin-4-yl)ethanol (1.13 g, 8.7 mmol) was dissolved in dry dimethoxyethane (7.0 mL). NEt 3 (2.0 mL, 14.2 mmol) was added in one portion. To the resulting mixture, a solution of isopropyl chloroformate in toluene (1.0M, 9.5 mL) was added dropwise, with vigorous stirring, over 5 min. A white precipitate formed, and the suspension was stirred at rt overnight. The white precipitate was filtered off, washed with EtOAc, and discarded.
  • Step B A sample of intermediate 26d (4.20 g, 19.5 mmol) was dissolved in dry CH 2 Cl 2 (30 mL), then NEt 3 (4.0 mL, 28.5 mmol) was added. The resulting mixture was cooled to O 0 C. Methanesulfonyl chloride (1.7 mL, 21.9 mmol) was added dropwise, with vigorous stirring, over 5 min. The ice-bath was removed and the resulting solution was stirred at rt for 30 min. The reaction mixture was added to water (40 mL) and extracted with CH 2 Cl 2 (2 x 40 mL). The combined organic extracts were washed with sat.
  • Step A Commercially available 4-pyridinepropanol (25 g, 182 mmol) was charged into a Parr-shaker flask and HCl in dioxane (4M, 100 mL) was added, followed by PtO 2 (4.72 g, 20.8 mmol). The mixture was shaked for 48 h under H 2 (60 psi). The mixture was then evacuated and placed under N 2 , filtered through celite and washed with H 2 O. Concentration of the filtrate afforded 3-(piperidin-4-yl)propan-l-ol hydrochloride (27a) as a yellow oil. The compound was used in the next step without further purification.
  • Step B The crude compound from Step A (22.3 g, 124 mmol) was suspended in dry DMA (100 mL), then NEt 3 (43 mL, 308 mmol) was added. The resulting mixture was cooled to O 0 C. A solution of isopropyl chloroformate in toluene (1.0M, 150 mL) was added dropwise. A white precipitate formed and the suspension was stirred at it overnight. The white precipitate was filtered off, washed with EtOAc, and discarded. The filtrate was concentrated in vacuo to yield isopropyl 4-(3- hydroxypropyl)piperidine-l-carboxylate (27b) as an oil.
  • Step C A sample of intermediate 27b (13 g, 56.7 mmol) was dissolved in dry CH 2 Cl 2 (107 mL), then EtN(Z-Pr) 2 (15 mL, 87.6 mmol) was added. The resulting mixture was cooled to 0 °C. Methanesulfonyl chloride (4.9 mL, 63.1 mmol) was added dropwise, with vigorous stirring, over 5 min. The ice-bath was removed and the resulting solution was stirred at rt overnight. The reaction mixture was poured into IM HCl and extracted with CH 2 Cl 2 . The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), and concentrated in vacuo to yield isopropyl 4-(3-
  • Step B Acid 28a (3 g, 11.7 mmol) was dissolved in THF (30 mL), treated with a solution of BH 3 in THF (IM, 23 mL, 230 mmol), and stirred at rt for 4 h. The solvent was then evaporated, EtOAc was added and the mixture was washed with IM HCl, and brine. The organic phase was dried over Na 2 SO 4 , and concentrated in vacuo to give isopropyl 4-(4-hydroxybutyl)piperidine-l-carboxylate (28b) as a colorless oil.
  • Examples 32-35 were synthesized by analogous methods from derivative 27 and appropriate alkylhalides.
  • Examples 38 and 39 were synthesized by analogous methods from derivative 26c and the appropriate acids.
  • Step A Commercially available 6-(methoxycarbonyl)-l,2,3,4-tetrahydro- isoquinoline hydrochloride (17.4 g, 76.4 mmol) was converted to methyl 2- (methylsulfonyl)-l,2,3,4-tetrahydroisoquinoline-6-carboxylate (40a) following the same procedure described for the preparation of intermediate 27c.
  • Step B Ester 40a (6.16 g, 22.9 mmol) was suspended in MeOH (60 mL) and a solution of NaOH (10%, 60 mL) was added. The mixture was stirred for 4 h. IM HCl was then added until a clear solution was obtained. The mixture was extracted with EtOAc. The aqueous phase was acidified to pH 1 with IM HCl and the resulting precipitate was filtered, washed with EtOAc, and dried to afford 2-(methylsulfonyl)- l,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (40b).
  • Step A Commercially available tert-butyl 2-(piperidin-4- yl)ethylcarbamate (1.91 g, 8.37 mmol) and NEt 3 (1.5 mL, 10.7 mmol) were dissolved in 1,2-dimethoxyethane (20 mL) and DMF (20 mL). A solution of isopropyl chloroformate in toluene (IM, 9.5 mL, 9.5 mmol) was added dropwise with stirring. The resulting mixture was stirred at it for 16 h. EtOAc was added, and the organics were washed with water, sat. NH 4 Cl, and brine, dried over MgSO 4 , and filtered.
  • IM isopropyl chloroformate in toluene
  • Step B Intermediate 41a (2.40 g, 7.63 mmol) was dissolved in CH 2 Cl 2 (5 mL). Trifluoroacetic acid (4 mL) was added and the mixture was stirred at rt for 2 h. The solvent was evaporated, EtOAc was added to the residue and the resulting solution was neutralized with sat. aqueous NaHCO 3 . The mixture was extracted with EtOAc.
  • Step A Mesylate 27c (3.83 g, 12.5 mmol) was dissolved in DMF (24 mL).
  • Step B Azide 42a (2.08 g, 8.18 mmol) was dissolved in MeOH (86 mL).
  • Step B Alcohol 43b (4.25 g, 21.1 mmol) was converted to isopropyl 4-
  • Step A Isopropyl 4-cyanopiperidine-l-carboxylate (47a) was prepared from 4-cyanopyperidine (1.36 g, 12.3 mmol) according to the same procedure described for the preparation of 26c, using EtOAc as solvent.
  • Step B Hydroxylamine (50% in water, 0.38 mL, 6.2 mmol) was added to a mixture of 47a (617 mg, 3.1 mmol) in EtOH (2 mL). The mixture was heated at 60 0 C for 1.5 h and the solvent was removed under reduced pressure. Water was added and the mixture was extracted with CH 2 Cl 2 . The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated in vacuo to afford isopropyl 4-(N'- hydroxycarbamimidoyl)piperidine-l-carboxylate (47b) as a white solid that was used in the next step without further purification.
  • Step B Isopropyl 4-(2-amino-2-(hydroxyimino)ethyl)-piperidine-l- carboxylate (48b) was prepared from 48a (560 mg, 2.66 mmol) according to the procedure described for the synthesis of 47b.
  • Method A To a solution of 51a (50 mg, 0.11 mmol) and 2-chloro-5-ethyl pyrimidine (74 ⁇ L, 0.61 mmol) in DMA (0.5 mL) was added EtN(Z-Pr) 2 (0.2 mL). The vial was sealed and heated at 150 0 C for 48 h. After cooling to it, the mixture was diluted with MeCN and filtered.
  • Method B The above mentioned starting material was heated at 150 0 C in microwave for 30 min in l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)- pyrimidinone (DMPU) in the presence of EtN(Z-Pr) 2 to yield the desired product.
  • DMPU l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)- pyrimidinone
  • Examples 52-57 were synthesized by analogous methods from derivative 51a and the appropriate heteroaromatics.
  • Step A A solution of 2-(methylsulfonyl)-l,2,3,4-tetrahydroisoquinolin-6- ol 3 (972 mg, 4.28 mmol) in CH 2 Cl 2 (40 mL) was cooled to -78°C, treated with NEt 3 (1.2 mL, 8.6 mmol) and trifluorometahnesulfonic anhydride (0.79 mL, 4.7 mmol). The mixture was stirred at -78°C for additional 30 minutes and then overnight at rt. Et 2 O was added and the mixture was washed with IM HCl. The aqueous phase was re-extracted with Et 2 O.
  • Step B 61a (1.2 g, 3.34 mmol), Zn(CN) 2 (431 mg, 3.67 mmol), and
  • Step C N'-Hydroxy-2-(methylsulfonyl)- 1,2,3, 4-tetrahydroisoquinoline-6- carboximidamide (61c) was synthesized from 61b (261 mg, 1.1 mmol) following the same procedure described for the preparation of 47b, using EtOAc as extracting solvent.
  • Examples 62 and 63 were synthesized by analogous methods from derivative 61c and the appropriate acids.
  • 6-Bromo-2-(methylsulfonyl)-l,2,3,4-tetrahydroisoquinoline (66a) was prepared from 3-bromophenethylamine according to the same procedure described for the preparation of 26b.
  • Examples 67 and 68 were synthesized by analogous methods from derivative 66a and the appropriate alkene.
  • Example 66 25 mg, 0.06 mmol was dissolved in EtOAc/EtOH (1:1, 3 mL) and subjected to hydrogenolysis (H-cube, full-hydrogen mode, Thales nanotechnologies) at 6O 0 C. Upon the completion of reaction, the solvent was evaporated and the crude product was purified by reverse-phase HPLC to yield the title compound (Example 69).
  • Examples 70 and 71 were synthesized by analogous methods from Examples 67 and 68.
  • Step A NEt 3 (10.4 mL, 74.6 mmol) was added to a solution of 4- hydroxypiperidine (5.82 g, 57.5 mmol) in EtOAc (50 mL) at rt. The resulting suspension was cooled to 0 0 C, treated with a solution of isopropyl chloroformate in toluene (1.0M, 69 mL) and stirred at rt overnight. The mixture was quenched with water and stirred for 15 minutes, until a clear solution formed. The organic phase was separated and the aqueous layer was extracted with EtOAc.
  • Step B Isopropyl 4-(methylsulfonyloxy)piperidine-l-carboxylate (72c) was prepared from 72b (1 g, 5.3 mmol) according to the procedure described for the preparation of 27c.
  • HF-pyridine (0.1 mL) was added dropwise to a suspension of 1,3- dimethyl-5,5-dimethylhydanthoin (34 mg, 0.12 mmol) in CH 2 Cl 2 (0.2 mL) at -78 0 C.
  • the resulting colorless solution was then treated with a solution of 75a (38 mg, 0.07 mmol) in CH 2 Cl 2 (0.2 mL) and stirred at -78°C for 30 minutes.
  • the mixture was then filtered through a plug of basic aluminium oxide (Brockmann I, Aldrich) and washed with CH 2 Cl 2 .
  • the solvent was evaporated and the crude material was purified on reverse- phase HPLC to yield the title compound (Example 75).
  • Step A NaN 3 (5.7Og, 87.7 mmol) was added in small portions to a solution of 6-methoxy-l-tetralone (15 g, 85.1 mmol) in concentrated HCl at 0 0 C. The resulting mixture was stirred at it for 4 h, then carefully poured into a cold biphasic solution of CH 2 Cl 2 (150 mL) and aqueous K 2 CO 3 (150 g in 300 mL). The organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 .
  • Step B A solution of 76a (2.14 g, 11.2 mmol) in dioxane (15 mL) was added dropwise at O 0 C to a solution of LiAlH 4 in THF (IM, 39 mL, 39 mmol) under Ar atmosphere. Upon completed addition, the mixture was heated to reflux overnight. After cooling to rt, sat. aqueous Na 2 SO 4 was added until the gas evolution ceased. The residue was filtered over celite, washed with EtOAc and discarded. The filtrate was concentrated to yield crude 7-methoxy-2,3,4,5-tetrahydro-lH-benzo[b]azepine (76b) that was used in the next step without further purification.
  • Step C A solution of 76b (1.98 g, 11.2 mmol) in HBr (48%, 20 mL) was heated to reflux for 4 h. After removal of the solvents, the residue was dissolved in EtOH and filtered to remove any insoluble material. The filtrate was concentrated to afford 2,3,4,5-tetrahydro-lH-benzo[b]azepin-7-ol hydrobromide (76c) that was used in the next step without further purification.
  • Step D Intermediate 76c (1.5 g, 6.14 mmol) was dissolved in dry CH 2 Cl 2
  • Step E A suspension of 76d (1.96 g, 6.14 mmol) in MeOH (40 mL) and
  • Step A To a suspension of 3-(piperidin-4-yl)propan-l-ol hydrochloride
  • Step B MsCl (14.3 mL, 0.184 mol) was slowly added to a stirred solution of 77a (43.6 g) in CH 2 Cl 2 (150 mL) and pyridine (27 mL, 0.184 mol) at 0 0 C over 30 min. The reaction was stirred at 0°C for another hour, then at rt overnight. The mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 100 mL).
  • 6-ol (3) (9.15 g, 40.3 mmol), tert-butyl 4-(3-(methylsulfonyloxy)-propyl)piperidine-l- carboxylate (77b) (12.9 g, 40.3 mmol) and Cs 2 CO 3 (16.34 g, 50.3 mmol) in ACN (150 mL) was heated at 80°C (oil bath) for 24 h under Argon. After cooling at it, the mixture was filtered and the filter cake was washed with EtOAc (200 mL).
  • Step D To a solution of compound 77c (22.42 g, 50 mmol) in CH 2 Cl 2 (150 mL) was slowly added TFA (30 mL) at O 0 C. After 30 min, the cold bath was removed and the mixture was stirred at it for 3 h. After removal of the solvent, the residue was taken up by 50 mL of saturated NaHCO 3 , and basified to pH ⁇ 10 by 20% NaOH.
  • Examples 78-99 were synthesized by analogous method from Example 77.
  • Step A A solution of 5,5-dimethyl-4-oxohexanoic acid (104a) (1.00 g,
  • Step C A mixture of 6-tert-butylpyridazin-3(2H)-one 104c was refluxed in
  • Step A A solution of isobutyronitrile (13.82 g, 0.20 mol) and hydroxylamine (50% in water, 49 mL, 0.80 mol) in 95% ethanol was refluxed overnight. The solvent was evaporated and the residual water was removed azeotropically with toluene to give iV-hydroxyisobutyrimidamide (121a) as a light yellow solid.
  • Step B To a stirred a suspension of sodium bicarbonate (2.80 g, 33.3 mmol) and 4-piperidinepropanol hydrochloride salt (2.00 g, 11.1 mmol) in water (1.5 mL), CH 2 Cl 2 (2 mL) was slowly added a solution of cyanogen bromide (1.42 g, 13.4 mmol) in CH 2 Cl 2 (3 mL) at 0°C (ice bath) over 1 h. The cold bath was removed and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH 2 Cl 2 (20 mL), basified with sodium carbonate (0.33 g), and dried over MgSO 4 .
  • Step A Cyanogen bromide (36 mg, 0.34 mmol) was added in one portion to a stirring suspension of sodium bicarbonate (0.15 g) and 2-(methylsulfonyl)-6-(3- (piperidin-4-yl)propoxy)-l,2,3,4-tetrahydroisoquinoline (77d) (200 mg, 0.283 mmol) in water (0.1 mL) and CH 2 Cl 2 (1 mL) at 0 0 C. The cold bath was then removed and the reaction mixture was stirred overnight at it. The mixture was then diluted with CH 2 Cl 2 (25 mL), washed with brine, dried over MgSO 4 and filtrated.
  • Step B A mixture of 4-(3-(2-(methylsulfonyl)- 1,2,3,4- tetrahydroisoquinolin-6-yloxy)propyl)piperidine-l-carbonitrile (123a) (188 mg, 0.50 mmol), ammonium chloride (37 mg, 0.70 mmol) and NaN 3 (37 mg, 0.566 mmol) in DMF (1 mL) was heated in a sealed vial at 80°C overnight. After cooling to rt, the reaction was quenched with water (10 mL) and the precipitate was collected by filtration.
  • reaction mixture purified by ⁇ PLC to give 6-(3-(l-(2-methyl-2H- tetrazol-5-yl)piperidin-4-yl)propoxy)-2-(methylsulfonyl)-l,2,3,4-tetrahydroisoquinoline (124) as a major product and 6-(3-(l-(l-methyl-lH-tetrazol-5-yl)piperidin-4-yl)propoxy)- 2-(methylsulfonyl)-l,2,3,4-tetrahydroisoquinoline (125) as a minor product.
  • Example 126 The title compound was prepared in a manner similar to Example 124 from Example 126.
  • Example 126 The title compound was prepared in a manner similar to Example 124 from Example 126.
  • Trimethylphosphonoacetate (0.1 mL, 0.69 mmol) was added dropwise to a suspension of NaH (23 mg, 0.57 mmol) in dry THF (0.5 mL) at 0 0 C under N 2 atmosphere. After stirring at rt for 30 minutes, a solution of compound 74 (50 mg, 0.11 mmol) in dry THF (0.3 mL) was added dropwise to the reaction mixture and the resulting solution was stirred overnight at rt. The mixture was then diluted with MeCN and filtered. The filtrate was purified by reverse-phase HPLC.
  • Example 129 A solution of Example 129 (8 mg, 0.02 mmol) in dioxane (0.5 mL) was added dropwise into a suspension of NaH (15 mg, 0.37 mmol) in dioxane (0.2 mL) at O 0 C under N 2 . The resulting mixture was stirred for additional 10 minutes at 0°C and MeI (0.05 mL) was added. The mixture was then allowed to warm to rt and stirred overnight. The mixture was diluted with H 2 O and MeCN and filtered. The filtrate was purified by reverse-phase HPLC to yield the title compound (Example 137).
  • Example 138 DAST (0.2 mL) was added to Example 129 (8 mg, 0.02 mmol) and the mixture was stirred at rt for 1 h. CH 2 Cl 2 and sat. aqueous Na 2 CO 3 were then added. The resulting mixture was extracted with CH 2 Cl 2 . The organic layers were combined, dried (Na 2 SO 4 ), concentrated and the resulting residue was purified on a reverse-phase HPLC to yield the title compound (Example 138).
  • 140a was synthesized from 139 (600 mg, 1.29 mmol) according to the procedure described for the synthesis of 51a; MS calcd. for [M+H] + Ci 9 H 29 N 2 O 3 S: 365.2; found: 365.2.
  • Step B 2-(3-(Benzyloxy)-2,4-difluorophenyl)acetonitrile (146b)
  • benzyl bromide 3.9 mL, 32.8 mmol
  • potassium carbonate 4.5 g, 32.8 mmol
  • potassium iodide 3 g, 18.04 mmol
  • acetone 20 mL
  • Step E 6-(Benzyloxy)-5,7-difluoro-2-(methylsulfonyl)-l,2,3,4- tetrahydroisoquinoline (146e).
  • 146d 270 mg, 0.8 mmol
  • dry DME 1.6 mL
  • boron trifluoroetherate 300 uL, 2.4 mmol
  • Step G 6-(3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-5,7- difluoro-2-(methylsulfonyl)-l,2,3,4-tetrahydroisoquinoline (146).
  • Examples 151, 158 and 159 were prepared by analogous method from example 146.
  • Step A 2-(3-Methoxyphenyl)-2-methylpropanenitrile (146a) .
  • a solution of KHMDS 0.5 M in THF, 120 mL was added dropwise to a solution of 3-fluoroanisole (5 g, 40 mmol) and isobutyronitrile (14.2 mmol, 160 mmol) in toluene (50 mL) at rt.
  • the mixture was then stirred overnight at 6O 0 C, and then cooled to rt, carefully poured into 1 N HCl and extracted with EtOAc.
  • the organic layers were combined, washed with water, brine, dried (MgSO 4 ), filtrated and solvents were removed under reduced pressure.
  • Step B 2-(3-Methoxyphenyl)-2-methylpropan-l -amine (147b).
  • a solution of borane in THF (80 mL, 1 M) was added dropwise to a solution of 2-(3- methoxyphenyl)-2-methylpropanenitrile (147a) (2.8 g, 16 mmol) in anhydrous THF (10 mL) at 0 0 C (ice bath).
  • the mixture was allowed to warm up to rt, stirred for 1 hour, and cooled back to O 0 C. MeOH was slowly added until gas evolution ceased.
  • the solution was concentrated and the resulting oily residue was added to IN HCl (60 mL).
  • Step C 6-Methoxy-4,4-dimethyl-l,2,3,4-tetrahydroisoquinoline (147c).
  • Step D 4,4-Dimethyl-l,2,3,4-tetrahydroisoquinolin-6-ol (147d).
  • a solution of 48% aq HBr (11.2 mL) was added to 6-methoxy-4,4-dimethyl- 1,2,3,4- tetrahydroisoquinoline (147c) (560 mg, 2.8 mmol) at rt.
  • the reaction vessel was sealed and the mixture was heated at 12O 0 C for 2.5 hours.
  • the mixture was cooled to rt, diluted with water and the aq HBr was removed under reduced pressure.
  • the crude material was triturated with EtOH and Et 2 O. It was filtered and solid was collected and air dried to afford 147d.
  • Step E 4,4-Dimethyl-2-(methylsulfonyl)- 1,2,3, 4-tetrahydroisoquinolin-6- ol (147e).
  • Et 3 N (889 uL, 6.4 mmol) was added dropwise at O 0 C to a solution of 147d (300 mg, 1.16 mmol) in CH 2 Cl 2 followed by the addition of methanesulfonyl chloride (200 uL, 2.6 mmol). After complexion of the reaction, water was added and the mixture was extracted with CH 2 Cl 2 . The organics were combined, washed with IN HCl, aqueous saturated NaHCO 3 , dried (MgSO 4 ), and filtrated.
  • Step F 6-(3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-4,4- dimethyl-2-(methylsulfonyl)-l,2,3,4-tetrahydroisoquinoline (147).
  • Example 147 was synthesized according to the procedure described for example 146 (Step G) from the corresponding phenol 147e and 4,4-dimethyl-2-(methylsulfonyl)- 1,2,3,4- tetrahydroisoquinolin-6-ol and 3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propyl methanesulfonate.
  • Example 145 was prepared by analogous method from example 147.
  • Step A l-Fluoro-2-methoxy-4-(2-nitrovinyl)benzene (149a).
  • a solution of aqueous NaOH (1.15 g in 4mL of water) was added dropwise to a mixture of 4-fluoro- 3-methoxybenzaldehyde (3.85 g, 25 mmol) and nitromethane (1.35 mL, 25 mmol) in MeOH (25 mL) at -1O 0 C. After complexion of the addition, the mixture was stored in a fridge at O 0 C overnight. The resulting mixture was then carefully poured into aqueous HCl (10%) and yellow precipitates were obtained. The heterogeneous mixture was then cooled for 30 min.
  • Step B 2-(4-Fluoro-3-methoxyphenyl)ethanamine (149b).
  • 149a 1.5 g, 7.6 mmol
  • THF 100 mL
  • the mixture was stirred at O 0 C for 15 minutes, warmed to it for 15 min and then refluxed for 2 hours. It was then cooled to O 0 C (ice bath), and Na 2 SO 4 10H 2 O (3.0 g) was slowly added.
  • Step C 7-Fluoro-6-methoxy-l,2,3,4-tetrahydroisoquinoline.
  • Step D 7-Fluoro-l,2,3,4-tetrahydroisoquinolin-6-ol (149d).
  • Step E Synthesis of 7-fluoro-2-(methylsulfonyl)- 1,2,3,4- tetrahydroisoquinolin-6-ol (149e).
  • 149d 750 mg, 3.0
  • Et 3 N 2.3 mL, 16.5 mmol
  • methanesulfonyl chloride 513 uL, 6.6 mmol
  • Example 149 2-(methylsulfonyl)-l,2,3,4-tetrahydroisoquinoline ( Example 149).
  • Example 149 was synthesized from 149e and 3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propyl methanesulfonate according to the prodcedure described for the synthesis of 146.
  • Step B (2-(4-(3-(2-(Methylsulfonyl)-l,2,3,4-tetrahydroisoquinolin-6- yloxy)propyl)piperidin-l-yl)pyrimidin-5-yl)methanol.
  • a solution of LiBH 4 in THF (2 M, 0.2 mL) was added slowly to a solution of methyl 2-(4-(3-(2-(methylsulfonyl)- 1,2,3,4- tetrahydroisoquinolin-6-yloxy)propyl)piperidin-l-yl)pyrimidine-5-carboxylate (50 mg) in dry THF (10 mL) at 0 0 C.
  • Step B 5-(4-(5-Methylpyridin-2-yl)phenethyl)-3-(2-(methylsulfonyl)- l,2,3,4-tetrahydroisoquinolin-6-yl)-l,2,4-oxadiazole .
  • Examples 164, 166, 168, 169, 190, 193, 194, 195 and 196 were prepared by analogous method from example 165.
  • Step A 6-(3-(4-Bromophenyl)propoxy)-2-(methylsulfonyl)-l,2,3,4- tetrahydroisoquinoline.
  • 2-(methylsulfonyl)-l,2,3,4- tetrahydroisoquinolin-6-ol (2 g)
  • 3-(4-bromophenyl)propyl methanesulfonate 2.5 g
  • Cs 2 CO 3 3.2 g
  • the mixture was stirred at it overnight, diluted with EtOAc (150 mL).
  • Step B 2-(Methylsulfonyl)-6-(3-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)propoxy)-l,2,3,4-tetrahydroisoquinoline.
  • Examples 168-170, 178, 180, 191 and 197 were prepared by analogous method from example 167.
  • Step A 3-terr-Butyl-5-(4-(chloromethyl)phenyl)-l,2,4-oxadiazole
  • N-hydroxypivalimidamide (0.45 g)
  • THF 25 mL
  • 4-(chloromethyl)benzoyl chloride 0.62 g
  • Et 3 N 1 mL
  • the resulting mixture was heated at 60 0 C overnight. It was cooled to rt, EtOAc (50 mL) was added and the mixture was washed with water, brine, dried over Na 2 SO 4 and filtered. Solvents were removed under reduced pressure to give crude product.
  • Step B 3-tert-Butyl-5-(4-((2-(methylsulfonyl)-l,2,3,4- tetrahydroisoquinolin-6-yloxy)methyl)phenyl)-l,2,4-oxadiazole (176)
  • 3-t ⁇ rt-butyl-5-(4-(chloromethyl)phenyl)-l,2,4-oxadiazole 25 mg
  • 2- (methylsulfonyl)-l,2,3,4-tetrahydroisoquinolin-6-ol (20 mg
  • Cs 2 CO 3 60 mg
  • DMF 2 mL
  • Step A 2-Isopropyl 6-methyl 3,4-dihydroisoquinoline-2,6(lH> dicarboxylate
  • DMF dimethyl l,2,3,4-tetrahydroisoquinoline-6-carboxylate
  • Et 3 N 1 mL
  • Isopropyl carbonochloridate 400 mg was added and the mixture was stirred at O 0 C to rt for 3 hrs.
  • the reaction was quenched by addition of a solution of aqueous NH 4 Cl and the mixture was extracted with Et 2 O (3x25 mL).
  • Step B Isopropyl 6-(hydroxymethyl)-3,4-dihydroisoquinoline-2(lH)- carboxylate
  • 2-isopropyl 6-methyl 3,4-dihydroisoquinoline-2,6(lH)- dicarboxylate 560 mg
  • LiBH 4 (1 M, 5 mL
  • the reaction mixture was then heated at 6O 0 C for 3 hrs to bring the reaction to completion.
  • the mixture was then cooled to O 0 C and water was added followed by the addition of aqueous NH 4 Cl. It was extracted with EtOAc (3x25 mL).
  • Step C Isopropyl 6-((methylsulfonyloxy)methyl)-3,4- dihydroisoquinoline-2(lH)-carboxylate
  • isopropyl 6- (hydroxymethyl)-3,4-dihydroisoquinoline-2(lH)-carboxylate 100 mg
  • CH 2 Cl 2 10 mL
  • methanesulfonic anhydride 100 mg
  • 2,4,6-collidine 0.1 mL
  • the mixture was stirred at O 0 C for 4 hrs and quenched with water (1 mL), washed with brine, dried over Na 2 SO 4 and filtered. Solvents were removed under reduced pressure to give crude product which was used directly for next step.
  • Step D Isopropyl 6-((2-(methylsulfonyl)-l,2,3,4-tetrahydroisoquinolin-6- yloxy)methyl)-3,4-dihydroisoquinoline-2(lH)-carboxylate 2-(methylsulfonyl)-l,2,3,4- tetrahydroisoquinolin-6-ol (45 mg), isopropyl 6-((methylsulfonyloxy)methyl)-3,4- dihydroisoquinoline-2(lH)-carboxylate (70 mg, crude from previous step), Cs 2 CO 3 (120 mg) and DMF (5 mL) was placed in a reaction flask.
  • Step A 4-Chloromethylbenzoyl chloride (I g, 5.29 mmol) was dissolved in dioxane (10 mL) and ethylbenzylamine (2.4 mL, 16.1 mmol) was added dropwise at it. A white precipitate formed instantaneously. The mixture was stirred at rt for 2 h, diluted with CH 2 Cl 2 and washed with sat. NH 4 Cl and brine. The organic phase was dried (Na 2 SO 4 ), concentrated in vacuo, and the crude was purified by flash chromatography to afford N-benzyl-4-(chloromethyl)-W-ethylbenzamide (179a) as a colorless oil. MS calcd. for [M+H] + C 17 Hi 9 ClNO: 288.1; found: 288.1.
  • Step B A sample of 179a (666 mg, 2.31 mmol) was dissolved in THF (5 mL). The mixture was cooled to O 0 C and a solution of LiAlH 4 in THF (I M, 2.31 mL, 2.31 mmol) was added dropwise. The mixture was then stirred at rt overnight then carefully quenched with saturated aqueous Na 2 SO 4 until no more gas evolution was observed. The mixture was then filtered through celite and washed with EtOAc. Concentration of the organic phase yielded N-benzyl-N-(4-(chloromethyl)benzyl)- ethanamine (179b), which was used in the next step without further purification.
  • Step A (2-Chloropyrimidin-5-yl)methanol
  • methyl 2-chloropyrimidine-5-carboxylate 17.0 mg
  • THF 5 mL
  • the mixture was cooled to -78 0 C and a solution of DIBAL-H in hexane (1 M, 1.2 mL) was added slowly.
  • the resulting mixture was stirred at -78 0 C to it overnight, then quenched with saturated aqueous Na 2 SO 4 .
  • the solution was filtered. Solvents were removed under reduced pressure to give (2-chloropyrimidin-5-yl)methanol.
  • Step B (2-(4-(3-(2-(Methylsulfonyl)- 1,2,3, 4-tetrahydroisoquinolin-6- yloxy)propyl)phenyl)pyrimidin-5-yl)methanol
  • Pd(PPh 3 ) 4 (2 mg)
  • dioxane (2 mL)
  • Na 2 CO 3 (1 M, 1 mL
  • Step C 6-(3-(4-(5-((2-Methoxyethoxy)methyl)pyrimidin-2- yl)phenyl)propoxy)-2-(methylsulfonyl)-l,2,3,4-tetrahydroisoquinoline
  • the solution was cooled to O 0 C and NaH (40 mg) was added portionwise.
  • Example 139 (30.0 mg, 0.06 mmol), NaOAc (6.6 mg, 0.08 mmol) and
  • Example 208 0.07 mmol was converted to the corresponding alcohol. Boc deprotection was then performed using the same procedure described for the preparation of 51a, and conversion to the title compound (Example 208) was achieved following the procedure described for Example 60. The mixture was diluted with MeCN and filtered. The filtrate was purified by reverse-phase HPLC to yield the title compounds (Example 208 and Example 209).
  • Step A tert-Butyl 6-hydroxy-3,4-dihydroisoquinoline-2(lH)-carboxylate
  • Step B tert-Butyl 6-(3-(4-(5-ethylpyrimidin-2-yl)phenyl)propoxy)-3,4- dihydroisoquinoline-2(lH)-carboxylate (214b)
  • DMF dihydroisoquinoline-2(lH)-carboxylate
  • Cs 2 CO 3 600 mg, 1.9 mmol
  • 3-(4-(5-ethylpyrimidin-2-yl)phenyl)propyl methanesulfonate 360 mg, 1.15 mmol
  • Step C 6-(3-(4-(5-Ethylpyrimidin-2-yl)phenyl)propoxy)- 1,2,3,4- tetrahydroisoquinoline (214) tert-Butyl 6-(3-(4-(5-ethylpyrimidin-2-yl)phenyl)propoxy)- 3,4-dihydroisoquinoline-2(lH)-carboxylate (410mg, 0.82 mmol) was dissolved in dioxane (2 niL). A solution of HCl in dioxane (4 N, 2 mL) was added and the mixture was stirred for 20 h. Solvent was removed under reduced pressure and the remainder was dried under high vacuum to afford the desired product as HCl salt. MS calcd. for [M+H] + C 24 H 28 N 3 O: 374.2; found: 374.2.
  • Step A 2-(Methylsulfonyl)-6-(3-(piperazin-l-yl)propoxy)-l,2,3,4- tetrahydroisoquinoline (216a)
  • Trifluoroacetic acid (8 mL) was added at it to a solution of 261 (500 g, 1.1 mmol) in CH 2 Cl 2 (32 mL). The mixture was stirred at rt for 30 mins. The solvents were evaporated and the residue was diluted with chloroform and then neutralized with sat. NaHCO 3 . The aqueous was extracted with chloroform (3x10 mL).
  • Step B To a solution of 216a (20 mg, 0.06 mmol) and triethylamine (16 uL, 0.11 mmol) in CH 2 Cl 2 (5 mL) was added 1-methylcyclopropyl 4-nitrophenyl carbonate (14 mg, 0.06 mmol) at O 0 C. The ice water bath was removed and the resulting mixture was stirred at rt for 18 h. The solvent was removed under reduced pressure and the crude was purified by flash column chromatography (EtOAc/hexane) to afford the title compound 216. MS calcd. for [M+H] + C 22 H 33 N 3 O 5 S: 452.2; found: 452.2.
  • Step A 4-(3-(2-(Methylsulfonyl)-l,2,3,4-tetrahydroisoquinolin-6- yloxy)propyl)phenol (219a)
  • Pd/C 10 wt %, 100 mg
  • the mixture was stirred under a hydrogen atmosphere for 30 minutes and then filtered through a pad of Celite. Removal of the solvents under reduced pressure afforded intermediate 219a as a white solid.
  • Example 219 was prepared by analogous methods described for example 218 from derivative 219a and 2-chloropyrimidine.
  • Example 220 Purification the crude by flash chromatography (SiO 2 , gradient elution with 2% to 5% MeOH in dichloromethane), followed by reversed-phase HPLC (water-acetonitrile gradient with TFA as ion-pairing reagent) and lyophilization afforded Example 220 as a white powder.
  • Example 123 using appropriate starting materials.
  • Step A l-(4-Bromophenyl)pyrrolidin-3-ol (222a)
  • a microwave reaction vessel was charged with l-bromo-4-iodobenzene (1.2 g, 4.25 mmol), pyrrolidin-3-ol (0.68 g, 7.8 mmol), Cs 2 CO 3 (1 g, 3 mmol), pyrrolidine-2-carboxylic acid (0.05 g, 0.43 mmol) and DMF (25 mL).
  • the mixture was irradiated in microwave at 16O 0 C for 30 min. It was cooled to rt, diluted with EtOAc (60 mL), washed with brine, dried and filtered.
  • Step B l-(4-Bromophenyl)pyrrolidin-3-yl methanesulfonate (222b)
  • Et 3 N 0.2 g, 2 mmol
  • MsCl 0.20g, 1.75 mmol
  • the mixture was stirred at 0 0 C for 3 h, and then water (1 ml) was added to quench the reaction.
  • the organics were washed with brine, dried, filtered. Solvents were removed under reduced pressure to provide the crude product.
  • 1,2,3,4-tetrahydroisoquinoline (222c) A mixture of l-(4-bromophenyl)pyrrolidin-3-yl methanesulfonate (0.16 g, 0.5 mmol), Cs 2 O 3 (0.2 g, 0.61 mmol), 2-(methylsulfonyl)- l,2,3,4-tetrahydroisoquinolin-6-ol (0.12 g, 0.53 mmol) and DMF (2 mL) was heated at 6O 0 C for 4 h under N 2 . The mixture was cooled down to it, diluted with EtOAc (20 mL) and water (5 mL).
  • Step D 2-(Methylsulfonyl)-6-(l-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)pyrrolidin-3-yloxy)-l,2,3,4-tetrahydroisoquinoline (222d)
  • Step E 6-(l-(4-(5-Ethylpyrimidin-2-yl)phenyl)pyrrolidin-3-yloxy)-2-
  • Step A 3-(4-(5-Ethylpyrimidin-2-yl)-3-fluorophenyl)propyl methanesulfonate (226a)
  • the intermediate 226a was prepared in a manner similar to example 249 from l-bromo-2-fluoro4-iodobenzene.
  • Step B The title compound 226 was synthesized according to the procedure described for the synthesis of example 146 from phenol 3 and mesylate 226a.
  • Examples 223-225 were synthesized by analogous methods from the corresponding phenols and mesylate 226a.
  • Example 123 using appropriate starting materials.
  • Example 229
  • Example 123 using appropriate starting materials.
  • Step B 6-(3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2-(2-
  • Example 232 was synthesized following the analogous method of the synthesis of example 231.
  • Step A 3-(4'-Butylbiphenyl-4-yl)propyl methanesulfonate (233a)
  • the intermediate 233a was prepared in a manner similar to example 167 (Step C) from 3-(4- bromophenyl)propan-l-ol and example 146 (Step D).
  • Step B The title compound 233 was synthesized according to the procedure described for the synthesis of example 146 from phenol 3 and mesylate 233a. MS calcd. for [M+H] + C 29 H 35 NO 3 S: 478.2; found: 477.8.
  • Example 234 was prepared by analogous methods described in example
  • Example 123 (16 mg, 0.038 mmol), l-(2- chloroethyl)pyrrolidine hydrochloride (38 mg, 0.22 mmol) and Cs 2 CO 3 (124 mg, 0.38 mmol) in DMF (1 mL) was stirred in a seal vial at 50 0 C overnight.
  • the reaction mixture filtered through a syringe filter and purified by ⁇ PLC to afford 235 as a white solid. MS calcd.
  • Example 123 using appropriate starting materials.

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